1. Field of the Invention
The present invention relates to the use of the amino acid glutamine in combination with additional nutrients in a composition for alleviating side effects of oncology treatment in a cancer patient comprising administering to the patient a daily regimen which comprises administering (a) at least one dose of an oral composition in unit dosage form which comprises L-glutamine, vitamin A, vitamin C, vitamin E, and selenium twice daily; and (b) at least four glutamine lozenges throughout the day which comprise about 2 grams of glutamine each, beginning 4-7 days prior to said treatment and continuing through said treatment. The daily regimen allows for physical contact of mucosal membranes with glutamine as well as systemic administration for alleviating the side effects of oncology therapy.
2. Description of the Prior Art
Skubitz et al. in U.S. Pat. Nos. 5,438,075 and 5,545,668 disclose an oral glutamine composition which is used to treat oropharyngeal mucositis in patients undergoing chemotherapy or radiotherapy. The patents disclose a method of alleviating stomatitis or esophagitis originating from treatment with chemotherapy and/or radiotherapy by administering the glutamine composition described in the patent.
Anderson et al. disclose a patient study involving administration of a glutamine suspension to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Anderson et al. conclude that low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis and decreased the chance of patients developing mouth sores as a consequence of intensive cancer chemotherapy. See Anderson et al., Cancer, vol. 83 pages 1433-9 (1998).
Ford et al. disclose the use of total parenteral nutrition (TPN) supplemented by nasogastric glutamine-supplemented tube feedings in pediatric cancer patients receiving intensive chemotherapy alone or in combination with bone marrow transplantation. During a study of patients, Ford et al. anticipated that early glutamine supplemented tube feedings in children receiving intensive chemotherapy alone or in combination with bone marrow transplantation would result in improved nutrition with fewer infections and lower cost than TPN-supplemented patients. In addition, a shorter hospital stay and improved quality of life are anticipated. See Ford et al., J Pediatr. Oncol. Nurs., vol. 14, pages 68-72 (1997).
Huang et al., in Int. J. Radiat. Oncol. Biol. Phys., vol. 46, pages 535-9 (2000), evaluate the influence of oral glutamine on radiation-induced oral mucositis in the radiotherapy of head and neck cancer. Pursuant to the study, they conclude that oral glutamine may significantly reduce the duration and severity of objective oral mucositis during radiotherapy.
3. Discussion of the Background of the Invention
Gut toxicity is often exhibited following bolus administration of anti-neoplastic agents, but is more common when these agents are administered via continuous infusion. Continuous infusion is becoming the preferred method of administration of oncology treatment agents because continuous infusion chemotherapy results in exposure of the tumor to cytotoxic drugs for a period of time longer than other methods of administration. Thus, continuous infusion is considered to be more efficacious than bolus chemotherapy for tumors with low growth fractions. However, it is clear that continuous infusion chemotherapy exhibits a toxicity profile different from bolus drug administration, and for some drugs this may be associated with increased mucositis. Mucositis is inflammation of mucous membranes including any region in an alimentary canal. For example, the continuous infusion of doxorubicin is associated with less cardiotoxicity than bolus administration, but often mucositis as a side effect limits the amount of drug administered. Similarly, for example, the bolus administration of 5-fluorouracil is associated with leukopenia, whereas gut toxicity, including stomatitis and esophagitis, is often exhibited when the drug is administered by continuous infusion over more prolonged periods or when combined with folinic acid. Stomatitis is inflammation of the oral mucosa.
The mechanism of chemotherapy-induced mucositis appears to arise from a combination of many factors. Presumably, chemotherapy damages the rapidly dividing immature intestinal crypt cells and more superficial immature mucosal cells in the oropharynx. In addition to this direct damage, it is theorized that, as the mature epithelial cells are sloughed, damaged immature cells are exposed to pancreatic and biliary secretions resulting in further intestinal damage. This damage contributes to mucositis.
The gut is among the largest repositories of lymphoid tissue in the body and the gut-associated lymphoid tissue has been termed GALT (See Enteral Nutr., vol. 14, pages 109S-113S, (1990)). The effects of chemotherapy on this lymphoid tissue may result in an additional disruption to the gut mucosal integrity, in addition to the direct effects of chemotherapy on the enterocytes. Other factors may also be involved; in normal individuals there is a constant and closely regulated flow of energy, mediated by various metabolites, among different tissues in the body (See Adv. Enzymology, vol. 53, pages 202-231, (1982)). Chemotherapy appears to directly, or indirectly, via decreasing nutrient intake, alter the production of glutamine which is necessary for the gut. This effect has been exhibited during catabolic illness when plasma glutamine concentration often falls. It is thought that a result of mucositis is the bacterial translocation across a malfunctioning gut epithelium which is believed to play a role in the gut-related toxicity of chemotherapy and radiotherapy and thus mucositis is exhibited.
In healthy, non-stressed individuals, glutamine is a neutral, non-essential amino acid. It is the most abundant amino acid, comprising 60% of the total free amino acid pool. Because glutamine contains two nitrogen moieties it may also be one of the most versatile amino acids. Much of the nitrogen transported from the skeletal tissues to the visceral tissues is done by glutamine. As a primary fuel for rapidly dividing cells including enterocytes, colonocytes, lymphocytes and fibroblasts, it is as efficient as glucose. Oxidized glutamine provides substrate for the synthesis of purines and pyrimidines needed for DNA, RNA, and mRNA and in the kidney glutamine is involved in acid-base balance through ammonia production.
During periods of increased metabolic stress, glutamine is freely released from skeletal muscle and intracellular glutamine concentrations fall by more than 50%. Roth et al. found that in patients with abdominal sepsis survival Was related to levels of free intracellular glutamine in the blood. See Roth et al., Clin. Nutr., Vol. 1, pages 25-41 (1981). Although the body can synthesize glutamine, it is now considered a conditionally essential amino acid during periods of catabolism. Physiological glutamine synthesis rates cannot keep up with the higher requirements for the amino acid during stress. Furst et al. have suggested that during periods of stress, 15-35 grams of supplemental glutamine may be needed to preserve muscle glutamine, maintain gut integrity, provide fuel for cells with rapid turnover and improve overall nitrogen balance. See Furst et al., Kidney Int., vol. 36, pages 5287-5292 (1982).
During the past 10 years, the role of glutamine as an immunomodulator has been emerging. Tumor growth is inversely related to host glutamine reserves. In this way, tumors act as glutamine traps. Cancer cachexia is marked by massive host skeletal glutamine depletion. In vitro evidence of the dependence of tumor growth on glutamine has deterred its use in the clinical setting. However, growing in vivo evidence suggests that supplemental glutamine actually decreases tumor growth by upregulating the immune system. Glutamine is a major fuel source for immune cells, especially lymphocytes and macrophages, both key types of immune cells. In addition, glutamine has been shown to be involved with bacterial killing by neutrophils.
Lymphocytes are one class of rapidly dividing cells that utilize glutamine as a primary fuel source. Glutamine is an essential component of lymphocyte cell division in vitro. Other amino acids or combinations of glutamate plus ammonia cannot substitute for glutamine. Natural Killer (NK) cells are cytotoxic lymphocytes capable of killing tumor cells as well as producing other cytokines. Tumors do not grow well in hosts with high NK cell activity. Optimal functioning of lymphocytes, including NK cells, is dependent on adequate supplies of glutamine and glutathione. Research has indicated increases in NK cell activity when supplemental glutamine is administered. See Klimberg et al., J. Surg. Res., vol. 63, pages 293-297 (1996).
Radiation enteritis remains a significant clinical problem for patients receiving ionizing radiation to the abdominal and pelvic areas. The mucosal injuries seen with radiation to these areas include destruction of crypt cells, decreased villous height, ulceration and necrosis of the gastrointestinal epithelium. See Berthrong et al., World J. Surg., vol. 10, pages 155-170 (1986). The mucosal injuries are manifested by abdominal pain, bloody diarrhea, malabsorption and in some cases bacterial translocation. Severe cases can be complicated by strictures, obstructions, perforations, and fistula formation.
The role of glutamine as a preferred fuel for the gastrointestinal tract is well known. See, for example, U.S. Pat. No. 5,039,704 to Smith et al. Research has delineated the role of glutamine as both protector before and healer after radiation therapy. It appears that glutamine exerts a positive effect through three distinct routes; as a primary cellular fuel for enterocytes, as a precursor for nucleotides needed for cell regeneration and as a source of glutathione, a potent antioxidant.
Oral glutamine taken prior to radiation appears to exert a protective effect by bolstering gut glutamine metabolism which is evidenced by an increase in the number and height of intestinal cells as well as an overall increased proliferation of cells. Taken during or after radiation, oral glutamine lessens the degree of damage and accelerates healing of the irradiated bowel by improving cell structure and upregulating gut glutamine metabolism. See Klimberg et al., Am. J. Surg., vol. 172, pages 418-424 (1996). However, oral glutamine alone is usually insufficient since patients experience difficulty in swallowing and retaining the administered glutamine.
As previously mentioned, cytotoxic oncology treatment often produces gastrointestinal injury resulting in mucositis, stomatitis and enterocolitis. The severity of these effects may preclude dose escalation and, in fact, may warrant dose reductions. Several beneficial effects of supplemental glutamine in chemotherapy induced enterocolitis have been recognized. These include improved nutritional status, decreased intestinal injury, decreased bacterial translocation, reduced endotoxemia and improved survival. See, e.g., Fox et al., JPEN, vol. 12, pages 325-331 (1988) Further studies have shown that supplemental oral glutamine can enhance the effect of methotrexate, an anti-neoplastic agent, while decreasing morbidity to the host.
Because of the high incidence of chemotherapy induced morbidity there has been great interest in finding agents that may increase tolerance to antineoplastic treatments. Skubitz et al., in J. Lab. Clin. Med., vol. 127, pages 223-228 (1996) describe a study on the effects of supplemental glutamine on chemotherapy induced mucositis. Chemotherapy agents used by Skubitz et al. include doxorubicin, etoposide, ifosfomide, and carboplatinum. Patients received twice daily glutamine supplemented swish and swallow solutions on days 1 through 28 of chemotherapy. Skubitz et al. found significant reductions in the level of mucositis as well as the duration of mucositis. Subjectively, the patients felt that the mucositis was less severe which is important as a quality of life issue.
One of the major effects of glutamine supplementation is its protective effect on the gut barrier. Glutamine is the major fuel for the gut enterocyte and glutamine deficiency will decrease the gut mucosal barrier function leading to xe2x80x98gut leakxe2x80x99. By protecting the gut barrier, patients undergoing chemotherapy and/or radiation are able to better respond to treatment because of increased energy and decreased levels of mucositis, stomatitis and cachexia.
Glutamine has been studied with regards to limiting non-gastrointestinal chemotherapy related toxicity and it has been found to increase the survival rate in cancer patients receiving cyclophosphamide. The glutamine supplementation maintained normal cardiac glutathione levels decreasing cardiotoxicity. See, e.g., Klimberg et al., Academic Surgery Conference (1993). It also has been reported that the use of oral glutamine may prevent paclitaxel-induced myalgias and arthralgias. See Savarese et al., J. Clin. Oncology, vol. 12, pages 3918-3919 (1998).
Traditional diets taken by mouth usually contain less than 10 grams of glutamine per day. During periods of severe metabolic stress or catabolic insult 20 to 40 grams of glutamine may be required to maintain homeostasis. Recent studies have shown glutamine to be more effective when administered via the enteral route. Ready to use enteral supplements are not supplemented with glutamine because of stability issues. Standard pills or capsules are expensive and contain very small amounts of glutamine (500 -1000 mg) relative to the daily dosages shown to be effective (30 grams). A powdered glutamine supplement is most desirous because it is cost effective, easy to use, well absorbed, well tolerated, and safe. Thus, a daily regimen to administer a powdered glutamine nutritional supplement painlessly and effectively is needed.
Furthermore, the incidence of malnutrition in patients undergoing anti-neoplastic treatments is well known. Cancer cachexia is exhibited by profound weight loss and is secondary only to macronutrient (protein, fat, and carbohydrate) deficiency, negative energy balance, and inefficient metabolism. Cachexia is the gradual bodily deterioration of muscle mass and weight loss. Cancer cachexia is the weight loss and deterioration of muscle mass associated with a flourishing tumor. It has been suggested that micronutrient (vitamin, mineral, and trace elements) deficiency is prevalent in cancer patients and that antioxidants may be particularly importance since radiation and chemotherapy, which damage both healthy and malignant cells, are oxidative processes. Because cancer cells do not absorb antioxidants as efficiently as healthy cells, it may be possible to support normal tissues with antioxidants while making the oxidative process more selectively toxic to malignant cells. Under conditions of antioxidant depletion, fewer oxidants are needed for injury to occur. The provision of antioxidant nutrients and precursors such as vitamins A, C and E, and selenium may offer protection to healthy cells against oxidative injury by antineoplastic therapy.
Therefore, a daily regimen including micronutrient and antioxidants as well as glutamine supplementation for alleviating cachexia, mucositis and stomatis in cancer patients is needed.
The present invention provides a method of alleviating mucositis, stomatitis, and cachexia in cancer patients by administering a daily regimen, to the patients 4-7 days prior to oncology therapy, of at least one oral unit dosage form of glutamine with micronutrients and antioxidants two times a day (e.g, vitamin A, vitamin C, vitamin E, and selenium) and at least four doses of glutamine in the form of a lozenge administered throughout the day.
In a preferred embodiment, the unit dosage form comprises about 7-12 g of L-glutamine, about 4,000-7,000 IU of vitamin A, about 100-300 mg of vitamin C, abut 50-150 IU of vitamin E and about 25-100 xcexcg of selenium.
In a particularly preferred embodiment, the unit dosage form comprises about 10 g of L-glutamine, about 6,500 IU of vitamin A, about 200 mg of vitamin C, about 100 IU of vitamin E, and about 50 xcexcg of selenium.
In a preferred embodiment, at least two unit dosage forms of the glutamine composition are administered twice daily to a patient in need thereof as a component of the daily regimen.
In an especially preferred embodiment, the twice daily administration occurs once in the morning and once in the evening.
In a preferred embodiment, at least three unit dosage forms of the glutamine composition are administered twice daily to a patient in need thereof as a component of the daily regimen.
In another preferred embodiment, at least three glutamine lozenges are administered throughout the day to a patient in need thereof as a component of the daily regimen.
In a particularly preferred embodiment, at least four lozenges are administered throughout the day to a patient in need thereof as a component of the daily regimen.
In another particularly preferred embodiment, at least five lozenges are administered throughout the day to a patient in need thereof as a component of the daily regimen.
In another particularly preferred embodiment, at least six lozenges are administered throughout the day to a patient in need thereof as a component of the daily regimen.
In another embodiment of the invention, the daily regimen is initiated 4 days prior to the oncology treatment, 5 days prior to the oncology treatment, 6 days prior to the oncology treatment, or 7 days prior to the oncology treatment.
Additional objects, features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims.